Alveolar macrophages in lung cancer: opportunities challenges

Abstract

Alveolar macrophages (AMs) are critical components of the innate defense mechanism in the lung. Nestled tightly within the alveoli, AMs, derived from the yolk-sac or bone marrow, can phagocytose foreign particles, defend the host against pathogens, recycle surfactant, and promptly respond to inhaled noxious stimuli. The behavior of AMs is tightly dependent on the environmental cues whereby infection, chronic inflammation, and associated metabolic changes can repolarize their effector functions in the lungs. Several factors within the tumor microenvironment can re-educate AMs, resulting in tumor growth, and reducing immune checkpoint inhibitors (ICIs) efficacy in patients treated for non-small cell lung cancer (NSCLC). The plasticity of AMs and their critical function in altering tumor responses to ICIs make them a desirable target in lung cancer treatment. New strategies have been developed to target AMs in solid tumors reprograming their suppressive function and boosting the efficacy of ICIs. Here, we review the phenotypic and functional changes in AMs in response to sterile inflammation and in NSCLC that could be critical in tumor growth and metastasis. Opportunities in altering AMs' function include harnessing their potential function in trained immunity, a concept borrowed from memory response to infections, which could be explored therapeutically in managing lung cancer treatment.

Keywords: immune checkpoint inhibitors; lung cancer; smoking; tissue-resident alveolar macrophages; tumor microenvironment; tumor-associated macrophages.

Figure 1

Spectrums of tumor associated macrophages. Tumor associated macrophages (TAMs) can develop from monocytes, monocyte-derived alveolar macrophages (MoAMs), tissue-resident alveolar macrophages (TRAMs), or interstitial macrophages (IMs) in the lung. TAMs exist as a spectrum of phenotypes from inflammatory to anti-inflammatory cells. Inflammatory macrophages are defined by higher expression of antigen-presenting and co-stimulatory molecules including CD80/CD86, CD40, MHCII, and secretion of inflammatory cytokines, whereas anti-inflammatory macrophages are immunosuppressive, expressing CD163 and Dectin-1, higher levels of CD206, and secretion of immunosuppressive cytokines and angiogenic factors. Typically, anti-inflammatory TAMs are more abundant in NSCLC.

Figure 2

MoAMs replace TRAMs after severe lung infection. Severe infection leads to the death of TRAMs but attracts monocytes, neutrophils, DC, and T cells from the blood stream to the alveolar space. Increased interstitial macrophages can be found in the lungs. After recovery, MoAMs replace the loss of TRAMs in the alveoli.

Figure 3

Tissue Resident Alveolar Macrophages in homeostasis and immune suppression in response to chronic inflammation. The production of GM-CSF from ATII cells supports AM survival, proliferation, and differentiation. Under homeostasis, AMs express high levels of pathogen recognition receptors (PRRs), such as toll-like receptors (TLRs) to rapid response to bacterial, and viral insults. Engagement of TLRs induces NFκB activation which stimulates inflammatory cytokines IL-6 and IL-1β production, and recruit neutrophils. Phagocytosing apoptotic cells stimulates suppressive signals IL-10, TGF-β, and PGE2 secretion mitigating tissue damage and inflammation. In contrast, cigarette smoke inhibits TLRs and phagocytic receptors dampening responses to viral and bacterial threats in AMs, while increasing CD206. Cigarette smoke stimulates IL-8 and CCL2 production, which recruits additional macrophages primed to secrete excessive ROS, MMPs, and other inflammatory cytokines, resulting in excessive neutrophils and causing tissue damage. Cigarette smoke generates nano-sized carbon which accumulates in AMs and penetrates mitochondria, inducing ROS and HIF-1α while decreasing PPARγ signaling.

Figure 4

PD-L1 expression and localization of macrophages in early and late stages of NSCLC. Tumor-associated macrophages express high levels of PD-L1 through activation of HIF1α, COX2 signaling, paracrine IFN-γ, autocrine TNFα, and extracellular vesicles (EVs) from tumor cells. In the early stage of NSCLC, embryonic-origin TRAMs are adjacent to the tumor cells. They surround the tumor mass preventing CD8 T cell infiltration, promoting FOXP3⁺Tregs, and inducing epithelial-mesenchymal transition of tumor cells. In the late stage of NSCLC, these TRAMs are in the periphery and MoAMs dominate the tumor.

Figure 5

Targeting macrophages to control tumor microenvironment. Therapeutic strategies aimed at controlling TAM in the TME fall into 1) controlling the number of TAMs either by anti-CSF-1R and chemicals such as clodronate, zoledronic acid, and Trabectedin to deplete the cells, or by chemokine blockades to decrease the recruitment of TAMs. 2) Functional-based reprogramming that targets the surface receptors/ligands. For example, increase phagocytosis by SIRPα, Siglec-10, and LILRB1/2 blockades; activate TLR and CD40 signaling by agonists; inhibit immunosuppression by targeting Trem2, CD163, and PD-L1. 3) Pan reprogramming that inhibits the intracellular key regulators such as PI3Kγ and HDAC to prevent TAM polarization. 4) Expression of engineered CAR in TAMs to recognize and phagocytose targeted tumor cells.